S. M. RICELVAIN AND THOMAS P. CARNEY
2802
was soluble in acid and contained no halogen (Beilstein test). It evidently was 6,6'-dimethoxy-8,8'-biquinolyl. Anal. Calcd. for C~OHI&O?: C, 75.93; H, 5.10. Found: C, 76.05; H, 5.10. 8-p-Aminophenyl-6-methoxyquinoline.-To 27.2 g. (0.097 mole) of crude tan-colored 6-methoxy-8-nitrophenylquinolines was added 145 ml. of 6 N hydrochloric acid and 88 g. (0.389 mole) of stannous chloride dihydrate. This mixture was heated under reflux on a steam-bath for forty minutes and the clear red solution which formed was allowed to cool to room temperature. A brown precipitate, probably the stannic chloride salt of the higher melting amine formed in the solution. This salt was filtered and decomposed with an excess of 40% sodium hydroxide to give a tan, alkali-insoluble solid. After this solid was filtered and washed free of sodium hydroxide, it was recrystallized from 400 ml. of 95% ethanol, the boiling solution being treated with Darco. On cooling th; amine The crystallized in light yellow prisms, m. p. 181-182 filtrates were evaporated and the solids obtained fractionally recrystallized. The total weight of amine so obtained the was 6.6 g. (27.2%). Recrystallized for anal:&, aminophenylme thoxyquinoline melted a t 180-182 Anal. Calcd. for C 1 6 H ~ 4 1 i ~ 0C,: 76.78; H, 5.64; N, 11.20. Found: C,76.66; H, 5.54; N, 11.41. I t was found that when the purified sample of 6-methoxy-8-p-nitrophenylquiiioline melting a t 206 O was reduced it gave a product identical with this amine, establishing its structure as 8-p-aminophenyl-6-methoxyquinoline. The filtrate from removal of the tin salt was made alkaline with excess 40% sodium hydroxide to give a redbrown solid. This solid was washed with water and then dissolved in 100 ml. of 95% ethanol. Cooling in an icebath for an hour gave only a trace of brown crystals. An equal volume of water was added to the filtrate and the milky solution so produced was again cooled. A dark brown precipita.te separated. This precipitate was again dissolved in ethanol, and the solution was diluted with water to cloudiness. The solution was heated, treated with Darco, filtered and cooled to give a white solid. T h p procedure was repeated until the solid f;sed a t 130-132 , although the melt was not clear until 140 . The weight of dry material so obtained was 5.5 g. (23%).
.
.
[COsTRIBUTION FROM
TIIE
Vol. A8
A portion of this fraction was recrystallized repeatedly from 75% ethanol. After five recrystallizations, the product melted constantly at 148-148 O and had the composition of an aminophenylmethoxyquinoline. Anal. Calcd. for ClsHllNzO: C, 76.78; H, 5.64; N, 11.20. Found: C,76.55; H,5.70; N, 11.36. 8 - ( p - 3-Diethylaminopropylaminophenyl)-6-methoxyquinoline.-A mixture of 11.24 g. (0.045 mole) of 8-paminophenyl-6-methoxyquinolineand 7.0 g. (0.047 mole) of 3-diethylaminopropyl chloride was heated in an oil-bath a t 130" for seven hours. The reaction mixture was cooled, the hard, glassy hydrochloride was treated with a solution of 6 g. of sodium hydroxide in 50 ml. of water and the mixture was extracted with ether. Quite a large amount of t h e reaction mixture was insoluble in ether and it was discarded. The ether solution was dried, the ethcr removed and the product distilled with a mercury vapor pump. The fraction boiling a t 200-208', a viscous, yellow liquid, was collected. It weighed 9.0 g. (0.0248 mole) representing a yield of 55%. Anal.11 Calcd. for C&29?V130: C, 76.00; H, 8.04. Found: C, 76.29; H, 8.20. Attempts to isolate a crystalline hydrobromide were unsuccessful, since even very slight exposure to moist air caused i t to turn into a red, semi-solid mass. The picrate was prepared in ethyl alcohol. I t initially formed as a liquid but recrystallization gave a red solid, m. p. 137l58O.
Anal. Calcd. for C3hH39N9Ol5: C, 51.16; H, 4.29. C, 50.92; H, 4.34.
Found:
Summary 8-(3-Diethylaminopropylaminomethyl) -6-methoxyquinoline and 8-(p-3-diethylaminopropylaminophenyl)-6-methoxyquinolinehave been synthesized and submitted for testing as potential antimalarial drugs. (11) Analysis by Mr. H. I,. Clark.
NOTREDAME,INDIANA
LABORATORY O F ORGANIC CHEMISTRY OF
THE
RECEIVED AVGUST 19, 1946
UNIVERSITY
O F WISCOXSIN]
Piperidhe Derivatives. XVII. Local Anesthetics Derived from Substituted Piperidinoalcohols BY S. If.MCELVAIN AND THOMAS P. CARNEY' The favorable pharmacological properties of the hydrochloride of y- (2-methylpiperidino)-propyl benzoate2 (I) (Metycaine) have led to its rather extensive clinical adoption for both topical and infiltration local anesthesia. More recently it has been used and recommended for continuous caudal a n a l g e ~ i a . ~ This compound has the additional clinical advantage of not showing the antagonism to the sulfa drugs that is characteristic ( 1 ) Eli Lilly and Company Post-doctorate Fellow. 1943-1944; present address: 'The Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. (2) McElvain, THISJ O U R N A L , 49, 2835 (1927). (3) Edwards and Hinyson, Am. J. Surg., 6 1 , 459 (1942); Hingson and Southworth, ibid., 68, 93 (1943); Hingson and Edwards, Anesfhcsia and Analgesia, 21, 301 (1942); J . A m . M e d . Assoc., 121, 225 (1943); ibid., 123, 538 (1943); Southworth, Edwards and Hingson, Ann. S w g . , 117. 321 (1943); Southworth and IIingson, i b i d . , 118, 8 4 5 (1943).
of such p-aminobenzoate esters as p r ~ c a i n e . ~ The general usefulness of I as a local anesthetic suggested a systematic study of the effects of variations of its structure on the pharmacological properties of the resulting compounds, in the hope that even more satisfactory local anesthetics might be discovcred. /CH2 --CHCH3 CH~ > N - - C H ~ C H ~ C H ~ O C ~ I1 \CH~-CH~ 0
I
For the purposes of this work, the structure of I was considered as composed of three structural (4) Cf. infer olio, Keltch, Baker, Krahl and Clowes, Proc. SOL. E r p . Biol. M c d . , 47, 533 (1941); Pfeiffer and Grant, Anesthesiology, 5, 605 (1946); Peterson and Finland, A m . J . M e d . S c i . , 207, 166 (1944).
Dec., 1946
LOCAL ANESTHETICSDERIVEDFROM SUBSTITUTED PIPERIDINOALCOHOLS 2593
units: (1) a substituted piperidino radical, (2) an alkylene group connecting this radical to the remainder of the molecule, ( 3 ) which in most cases is a n acyloxy group. Ninety compounds containing this basic structure have been prepared and are listed in Table I (no. 1 is the previously described compound I), together with the chemical and certain of the screening pharmacological data pertaining to them. The duration of topical anesthesia (T) was determined by application of a solution of the anesthetic in the per cent. shown to the rabbit’s cornea subcutaneous anesthesia (S) was determined on the guinea pig’s skin. These pharmacological data were kindly furnished by X r . Charles L. Rose of the Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. X more complete report of his pharmacological evaluation of these piperidine derivatives will be published elsewhere. The compounds listed in Table I may be conveniently divided into five groups. Those in the first group (nos. 3-54), with four exceptions, are various esters of y-(2-methylpiperidino)-propyl alcohol; the exceptions, nos. 47-50, have an ether or ketonic residue instead of an acyloxy group attached to the alkylene radical. In the second group, nos. 53-62, are esters of substituted piperidinopropyl alcohols containing a single alkyl substituent (other than the %methyl) in the piperidine nucleus and having those acyloxy groups found to be most advantageous in the preceding group. The members of the third group, nos. K - i 7 , differ froin those of the preceding groups by containing ;t tliinethylpiperidino rather than a monoalkqlpiperidino substitutent. The compounds in the fourth group, nos. 7S-79, cantain the 2,4,G-triiiic.thyl]~iperidinonucleus. The members of the fifth group, nos. S0-90, represent variations of the alkylene groups. The methods of preparations given in ’l’able I refer to general procedures, which are clescribed in the Experimental part. Discussion of the Pharmacological Data.-A study of the pharmacological data for the groups of closely related compounds t h a t appear in Table I leads t o the conclusion t h a t certain structural characteristics may be related fairly satisfactorily to one pharmacological property : the production of topical local anesthesia as measured by the application of a dilute solution of the compound to the rabbit’s cornea. The other pharmacological properties, infiltration anesthesia and toxicities, dcpcnding as they do upon unknown ratw o f absorption, metabolic destruction and elimination of the tested compounds, do not appear amenable to even an approximate correlation with structure. This is particularly noticeable in the toxicities, where a group of compounds may have similar intravenous toxicities but show widely d!fferently subcutaneous toxicities. Such deviatioiis from regularity necessarily limit the discusioii of these data to noting certain trends in the topical anesthesia values and pointing out
those few fortunate combinations of structural features that produce a generally favorable pharmacological behavior. The introduction of methyl, isopropyl or halogen substituents (nos. 2, 3, 5-s) into the phenyl group of I causes no marked improvement in the pharmacological properties; however, a p-phenyl substituent (no. 4) causes a marked rise in the anesthetic action with a simultaneous lowering of the intravenous toxicity. The hydroxyl substituent causes an improvement in the pharmacological action only when i t is in the o- or m-position (nos. 9 and 10). Aisa p-substituent (no. 11) this group causes the molecule to lose its topical anesthetic action as well as to become more toxic. This is particularly noticeable in no. 12, which has both o- and p-hydroxyl groups. The alkoxy substituents show no advantage to the o-position, in fact the p-substituents appear t o give superior pharmacological properties to the compounds (cf. nos. 13 and 14, 19 and 20, 12 and 33). The compounds (nos. 20-30) containing tht: higher 9-alkoxy substituents in the benzoate poi tion of I produced such profound topical anesthesia that they had to be applied in more dilute solutions to obtain comparable values; 156 solutions of these compounds produce indefinite anesthesia of the rabbit’s cornea. The toxicities of these compounds are interesting. While in general their intravenous toxicities are as low or lower than that of I, their subcutaneous toxicities are usually much higher. h particularly favorable combination of pharmacological properties, however, appears in the p-cyclohexyloxybenzoate,no. 2 i ; i t is very effective for anesthesia and also has surprisingly low intravenous and subcutaneous toxicities. The separation of the phenyl group froiii tlir carbalkoxy group by one or more carbons (nos. 84-40) or by a carbon and an oxygen (no. 41) usually destroys the topical anesthesia, althotigli ii,filtration anesthesia is retained; however, the P-butoxyphenyl acetate (no. 37) and the diphenylacetate (no. 40) do show some topical anesthesia. Of the three non-aromatic esters it is interesting to note that only those with cyclic structures (nos. 42 and 43) possess any anesthetic action and texicity ; the myristate (no. 44) is devoid of any anesthetic action and shows an extremely low toxicity. The carbamates (nos. 4.7 and 46) have no advantage over the benzoate I. The nun-ester compounds (nos. 47-30) are of interest because they show that the ester structure is not essential for local anesthetic action. Two o f thc. ethers show some infiltration anesthesia, while the ketone (no. 50) produces topical anesthesia comparable to I. Each of these coinpounds has as high toxicity as do the Inore potent anesthetics with an ester structure. The miscellaneous esters, nus. 31-31, have no noteworthy phariiiacological properties except possibly the extreinely low intravenous toxicity of the nicotinic ester, no. 32.
2594
S. M . MCELVAIN AND THOMAS P. CARNEY
Vol. 68
TABLEI HYDROCHLORIDES OF VARIOUSLY SUBSTITUTED PIPERIDITES, THEIRLOCALANESTHETICACTIONSAND TOXICITIES -Pharmacological
C H ~ C H Z C R ? C H Z C H ( C H ~ ) N ( C H Z ) ~ Rc HC~ hlolecular formula
.
Chemical data Md p . . %. Ionic C1 C. Prep.a Calcd. Found
CiTHzsC1NOz 182-184 CigHaoCINOz 165-166 C Z Z H Z ~ C ~ N O 185-187 S ClsHuClzNOr 213-214 CisHirBrClNOi 225-227 CisHzaClINOz 153-155 CisHzaClINOz 238-240 CiaHzrC1P\'O8 145-146 CisHz4ClNOa 189-191 CiaHzaClXOa 130-132 CisHrrClNOa 190-192 150-152 CoHznClNOa C17HzsCINOa 174-175 183-184 CisHwClNOs CisHaaClP\'Os 162-163 177-179 CisHanClNOa 155-156 CioHzsClNOs 103-105 CmHaClNO: 147-149 CmHazC1h703 175-176 CzoHnClSOa 1.53-155 CzoHazClNOa 134-155 CnHa1ClN0s 145-146 CziHa4ClNOa 160-162 CznHasClNOa 136-139 CzzHsaClNOa CnHa4ClNOs 178-180
A A A B
A A A A B B
B B A A A B B B B A B
R B B B
B B
11.37 10.43 9.48 10.67 9.42 8.34 8.34 11.30 11.30 11.30 10.76
11.35 10.52 9.51 10.67 9.36 8.31 8.13 11.29 11.15 10.92 10.77 10.82 1 0 . 8 5 10.82 1 0 . 8 4 10.37 10.42 9.96 9.83 9.96 9.87 10.02 9 . 9 5 9.59 9.54 9.59 9.61 9.59 9.55 9 59 9.51 9.24 9.24 9.24 9.24 8.91 8.86 8.91 8.97 8.88 8.96
Anesthesia dur., min. T b %sol. SC 10 9 9 80 10 15 9
1 1 1 0.5
12 21
1
1 1 1
1 1 40 0 1 8 0 1 8 1 13 1 24 1 40 1 40 1 30 1 30 0 . 5 39 0 . 5 80 0 . 5 50 0 . 5 50 0.25 50 0 . 2 5 83 0 . 2 5 37 55 0 . 1 37 20 0 . 1 23
9.14 8.65 8.42 8.69 8.79 9.00 11 38 10.92 10.25 9.11 10.35 10.72 9.09 10.84 11.62
30 25 50 40 35 22 0 0
B
9.09 8.78 8.48 8.78 8.82 9.19 11.37 10.82 10.37 9.24 10.43 10.88 9.14 10.82 11.67
103-19.5
I3
11.12
11.34
0
1
107-109 CzaHtsClNOz 216-217 CisHzaClNzOz C ~ O H ~ I C I N ~ O172-175 S 86-88 CisHzsClNO 145-147 CiaHzrClhTO 105-108 CieHzsC1hTO 175-178 CisHz4ClNO 105-168 CisHzrClNOL3 171 172 ViaHzaClNzOi
A
8 65
I)
11.34 14 9 . 7 0 18 14.37 0 13.1.5 n 12.41 0 12..59 1.5 10.1~0 11.79 0
1 0.5 1 I I 1 1
A A
8.78 11.34 9.77 14.19 13.11 12.49 12.58 in.7.i 11.88
Ci4HnCINOa
126-128
A
12.32
12.16
CirHnClNOzS
155-156
A
11.66
11.59
CzoHazClNOs CeHnClNOi CiaHzClNOz CzoHazClNOz C?oHnClSOz CnHaiClNO? CnIIzsClNOz
149-151 167-169 156-158 151-153 169-170 142-143 181-183
A A
9.59 9.68 9.59 9.71 10.88 10.83 10.02 9.93 10.02 9.86 9.57 9.64 10.88 Iu.91 I O O ? lO.(JO
CzzHzaCINOs 157-159 CzaHaoClNOa 142-144 145-147 CzrHnClNOa 203-204 CzaHzoClN01 161-162 CzaHzsClNOa im-151 CzoHaClN01 129-131 CirHzsCINOz ll6-149 CiiHmClNOa C I R H ~ ~ C I N O I 110-113 91-93 Cz1HuClNO: 134-136 CiqHaoCINOz 97-100 CisHzClNOz 148-150 CzaHaoClNOz 110-112 CirHzaClNOa 121-123 CisHinCINOz CoHaiClNOz
B B B B B
,n A B A B B
B B A
E E D
n TI 13
A C A C C
22 f 1 25 * 1 29 f 1 35 1 3 25 * 2 28 * 2 23 * 1 48 + 1 34 * 1 32 2 18 * 1 15*2 23 * 1 22 * 1 21 * l 15 * 1 26 * 2 27 * 2 12 * O 22 * 2 32 * 1 22 * o 24 * 2 31 * l 23 * 1 27 2 54 * 4 f
* 65
120 f 6 115 * 2 217 + 7
177 161
* 11 * 23
270 f 2 1 202 * 26 222 369 447
* 17 f f
48 22
22 25
50
31
0.25
30 28 7 74 23
0
i
3
I
15
1
8
117 + 'l 22 +:! 24 * I 18 1 0 2.5at I8 * 3 32 + 5 42 t i ino 3
0
1
5
3h*1
5
1
35 0 . 5 37 0 . 5 10 1 12 0 . 5 8 0.5 0 0.5 3 0.5 13 0 . 5
589
156 * 17 35 * 2 53 1 2 187 * 11 272 * 28 26 * 2 233 ==! 1 46 * 2 135 * 24 9 + l 30 * 2 32*Z 800 * ri4 74 * 4 1550 + 1x3 2x5 * I S 4214 275 * 21 20 * 5 306 d= 30 18 * 1 52 ' =4 2 OD0 * 117 27 + 1 .3h * 2 570 * 56 40 * l
0.25
0.25 0.25 0.25 1 1 1 o 1 25 1 0 1 0 1 18 1 0 1 0 1
dataL. D.60 * S.E. m.g/kg. in mice IntraSuhvenous cutaneous
lh I6
26
*
1
27 + 2 27 * 1 34 * 1 19 * I 18 * 1 22 * 2 98 I ?I, + 1 f
2!10
:{H
l i i i. I I to9 1 9
2311 500
* 23 *
11
420
i
ID
730
* 43
Dee., 1946
LOCAL ANESTHETICSDERIVED FROM SUBSTITUTED PIPERIDINOALCOHOLS 2595 TABLE I (Concluded)
----
(CI~B)~C~H~S(CH~)~OCOR.HC~ Positmn Molecular No. of CH3 R = formula 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77
78 79
R = -CeHs -CaII~OH(o)
CH3--C:,HgX-S-OCOR Position of No. CH3 80 2 81 2 82 2 83 2 84 2 85 3 86 4 87 4 88 4 89 4 90 2
CisHsClNOz CiaHziClNOs HCI
x=
178-180 177-179
A
B
% Ionic C1 Calcd. Found 11.37 11.18 10.82 10.68 11.37 11.36 10.82 10.75 11.37 11.24 10.82 10.89 11.37 11.32 10.82 10.71 9.24 9.02 8.68 8.78 8.65 8.75 10.31 10.20 10.88 10.79 9..96 9.79 1 1 . 3 3 11.27
Anesthesia dur., min. T b %Sol. SC 5 1 15 1 16 1 19 1 45 12 1 15 1 27 1 GO 23 1 39 30 0 . 5 50 0 25 60 0 2 5 0 1 2 0 1 11 0 1 3 0 1 3
10.88 10.37
21 15
1
10.86 10.25
-
Chemical &la--'5Ionic C1 Molecular M. p., '(2.5 Prep.0 Calcd. Found formula R = 11.37 11.43 Ci~HzaClNOz 135-137 A -CsHs A 10.88 10.79 -caHa CISHZSCINOZ117-119 10.43 10.37 CinH3oClNOz 112-114 A -caHa 11.91 11.70 C I ~ H Z I C I N ~174-176 Z A -cEHa 9.59 9.45 A -csH*OC~Hs(fl) CaoHaaClNO~ 154-156 9.24 9.59 A - c s H a o c ~ H ~ ( P ) Ca1HuClN0a 111-114 11.37 11.33 CiiHzsCINOz 162-165 A -csHs A 10.89 11.10 -csHa CiaHmCINOz 190-192 10.89 10.89 CisHzsClNOq 197-200 A -CsHs 8.91 9.07 Cz2HasCINO3 120-123 A -CaHaOCdHg(P) 10.82 10.71 Ci~HzsClNOa 118-120 D -c6Hs ,----
-(cHZ)4-(cHz)6-(CHz)s-CHzC!H(CHs)---.CHZC!H(CH,Y-CH(OHI)CHZCHF -CH(CH&)CHzCHz---CHzC:H(CHdCH(CH&-CHiC(CH3)zCHz--CHzC(CHa)zCH-(CHz)zO(CHz)2-
--Pharmacological Chemical data-hl. p., "C. Prep.a 151-153 A B 144-146 A 179-181 B 154-156 A 144-147 B 154-166 A 168-170 B 155-157 A 155-156 142-145 B 149-151 B A 186-187 A 117-119 83-86 A A 157- 158
1 1
32
Data--L. D.sa * S. E. m . g /kg. in mice IntraSubvenous cutaneous 35 * 2 1600 * 6 9 18 * 1 345 * 2 9 28 * 1 20 * 1 410 * 4 8 23 * 1 3 6 5 = 21 21 - 1 21 * 1 35 =t 1 3% * 27 24 * 1 l f i 0 * 16 32 1 2 8(10 = "0 33 * 3 45+3 2 5 0 * 12 710 * 3 5 28*l 630 i 39 37*3 ll5*G 330 * 39
13 27
*1 *1
---PharlnacolrigicaI
510
* 21
data-
,I,.D so = S IS. Anesthesia mg.;kg. in mice D u r . , min. intraSubcuT b % snl, S C \ - e m u s tanenus 7 1 20 1 17 1 17 * I 15 1 2s * 1 3 1 0 36 * 2 cal5OO 0 1 0 141 * 2 ca 800 GO 0 . 5 31 - 2 17 1 18 * 2 35 1 21 * l 27 *2 8 1 1 36 %t 2 30 1 15 21) * 5 ' a 1,;oo
a Preparatioiid procedure described in Experimental part. Topical anesthesia of the rabbit's corm:a. ous anesthesia of the guiiiea pig's skin. Eyes closed due to irritation; anesthesia value indefinite.
Suhcutarie-
llinong the other monoalkylpiperidino deriva- pharmacological properties over the corresponding tives (nos. 5;;-62) i t may be noted that the p- 2-methylpiperidino derivatives (nos. I .mtl 9 ) . The variations of the alkylene radicals iu coiiib u t o x y b e i i z o a . t c > sof the :1- and 4-inethylpiperidinopropyl alcohols (nos. 33 and 56) are as potent as pounds 80-90 show some striking effects. Lengthanesthetics as. is the corresponding 2-methylpiper- ening of the carbon chain that joins the nitrogen idino dcris-:itiw (no. 20). However, the replace- to oxygen (nos. 80-82) causes no niarked change ment of t h v methyl substituent of the piperidine in pharmacological action. However. shortening tiucleus or 1 by higher alkyl groups produces no an alkylene group to a two carbon chain, which iriarke(l i i i i p r o v c i i i c ~ t i tin pharmacological proper- carries a methyl substituent, practically destroys the anesthetic action of the benzoate and pties. The cliinetf-iylpiperidinoderivatil-cs (nos. 68-77) butoxybenzoate (nos. 83-54). That this marked show no advantage over the corresponding 2- change in pharmacological properties is due to t hc iiic~thylpipcritfinoderivatives unless the dimethyl shortening of the carbon chain of the alkylene siihstituents are in the 2,G-position. Then the ben- group is shown by return of strong anesthetic zoates (cf. nos. 1 and (in), the p-phenoxybenzoates action to compounds 83 and 86, which have a (nos. 2X and 7 2 ) and the p-amyloxybenzoates (nos. three carbon alkylene group similarly substituted 23 and 73) show noticeably greater anesthetic ac- by a methyl group. Indeed, unsymmetrical subtion with approsinlately the same toxicities ; how- stitution of methyl groups in the alkylene chain ever, the corresponding salicylates (nos. 9 and 70) appears to enhance anesthetic action (cf. nos. 87 and the p-l~ut.ox~benzoates (nos. 30 and 71) do not to 1 and 86), while symmetrical substitution of have very diffcrent pharmacological properties. the inethyl groups lowers the activity (cf. nos. S8 Among. these dirrieth~lpiI,eridino derivatives, the to 1; S9 to 30 and 56). Finally, the interruption very low suljcataneous toxicity id the 3,,3-di- of a four carbon alkylene group bi a i oxygen riiethylpi~,eridir1~11,rc11j~-l benzoate t n o . appears to improve the anesthetic actic)ii as a be notcAcI. '1'11~ t i ~ i i i i ~ t l i ~ l j ) i ~ substitiitinis i c ~ i ~ ~ i ~ i ~ ~ comparison of the pharmacological 1)rqvrties of in tiits, ;>; r , i d :!I 1)rodiiw no i i i i p r i ~ w t i i e i i t it1 110. 90 with those of no. SO will show.
2596
s. M. MCELVAINAND THOMAS P. CARNEY Experimental
Vol. 68
pipecoline hydrochloride, 12 g. of paraformaldehyde, and 200 ml. of isoamyl alcohol. The mixture was stirred and heated to 130" for one hour and then 40 g. of acetone was added over a period of thirty minutes. After two hours of heating, a n additional 12 g. of paraformaldehyde was added. Stirring and heating were continued for an additional three hours after Trhich the isoamyl alcohol was distilled off under diminished pressure. The solid residue was dissolved in water, and this solution extracted with ether. The separated aqueous layer then was made basic with sodium hydroxide, a n d the ainiiioketoiie extracted with ether. The ether layer was dried over sodium sulfate and distilled. A yield of 22.5 g. of the desired ketone was obtained. (2) Into a 500-ml. flask, equipped as described iu ( l ) , TABLE I1 were placed 40 g . of 8-pipecoline, 39 ml. of concentrated ALKPLPIPERIDINES hydrochloric acid, and 4 3 g. of 37% aqueous formaldehyde. The mixture was heated a t 100" for one hour and'then 40 Alkyl Bd P., ;I Z"l> C. substituent g. of acetone was added over a period of thirty minutes. The mixture was stirred and heatrd for three hours more, 117 1 4495 ,"-Methyl after which an additional 20 g. of aqueous lormaldehyde 1 4471 12s 3-hlethyl a i i t i 10 g. of acetone xwre add?(!. ScirrinL and heating 12; 1 . i:is2 I-~iethyl dditional hours. About 75 nil. were continued f ~ i threc 1.4430 3,1-Drnicthyl 137 of liquid was then distilled off t o remove unreacted acetone and formaldehyde, after which water was added to the 1.4442 136 2,5-Dimethyl residue, and this solution extracted with ether. The water 1.4408 129 2,fi-Dimethyl layer was then made basic with sodium hydroxide and rs143 1.4385 2,4,6-Trimethyl tracted with ether. The ether layer was dried over 1.4524 163 2-1sopropyl sulfate, and distilled. A yield of 26 g. of the aminoketone was obtained. 1,41378 174 4-Isopropyl The properties, method of preparation, yields, and 212 1.4549 2-%-Amyl analyses of the various rnethylpiperidinoaldehydcs and 1.3GOU 205 2- (3-Pentyl)a ketones prepared in this work are listed in Table IV. 1. 4360 230 %-Hexylb Substituted Piperidinoalcoho1s.-The substituted piperi a Calcd. for Cl&IzlN: iY, 9.02. Found: N , 9.12. dinoalcohols xere prepared by three general methods : (1) by the condensation of a chlorohydrin with a substib Calcd. for CIIH:&: N, 8.28. Found: N, 8.08. tuted piperidine, ( 2 ) by the reduction of an aldehyde or Chlorohydrins.--The chlorohydrins used in this work ketone obtained from the Mannich reaction, and (3) by were prepared from the corresponding glycols by the pro- the reaction of a substituted piperidine with propylene cedure described6 for the preparation of trimethylenc oxide. The following preparations illustrate tlicse chlorohydrin. It was found desirable to employ somewhat methods. highcr reaction temperatures for the higher glycols. The ( l a ) 3-(2,6-Diniethylpiperidino)-propyl Alcohol: 111 j)ropertic\, reaction temperatures used for thc preparation, this method two moles of the piperidine per mole of cliloroaiid the yiclds of the chlorohydrins are listed iii Table 111. hydrin were used, t h e second niole of the base being uscd t o take up the hyclrogcn chloride formed in the rcaction: Tnn1.o I11 111 a 100-nil. flask equipped with a stirrer aiitl reflux contleiiscr werc placed 26 g. (0.23 mole) of 2,ti-tlitnethylCIfLOROHYDRINS I)iperidirie arid 10.8 g . (0.115 mole) of tritnethy!ciic chloroKract iuti hydrin. Ail oil-batli hurrounding the flask was heated to B. p.. ' C . temp., Yield. Chlorohydrin (mni.) T L ~ D oc. % 160" for one hour, then to 175" for two hours, aiid iinally tlic temperature \:as raised to 210" over a period of one Tetramcthyleiie 57(10) 1.4502 165-170 10" hour. The reaction mixture on cooling set to a semi-solid 23 Pentamethyleiieb 103 (8) 1.4518 180-186 mass. Ether was added and the insoluble 2,6-diniethylHexamethylene 112 (12) 1.4541 195-200 31 piperidine hydrochloridc filtered off. Distillation of the filtrate yielded I O g. of 3-(2,6-dimethylpiperidiiio) -propyl 2-Ethyl-3-chloroalcohol. hexanol" 121 (30) 1.4559 200-205 30 ( I b ) 3-(2,4-Dimethylpiperidino)-propgl Alcohol .-In a The major product from the preparation of this this method the equimolecular proportions of the clllorochlorohydrin was tetrahydrofuran. Calcd. for C ~ H I I - hydriii and the piperidine are condensed in the presence of Calcd. for CS- potassium carbonate: In a 100-ml. flask equipped as it1 C10: C1, 28.91. Found: C1, 28.75. Hl,CIO: C1, 21.53. Found: C1, 21.33. ( l a ) were placed 13.2 g. (0.12 mole) of 2,4-dimethylMethylpiperidinoaldehydes and Ketones by the' Man- piperidine, 11 .0 g. (0.12 mole) of trimethylene chloronich Reaction.-For the preparation of the pipcridino- hydrin, and lti g. of anhydrous potassiuni carbonate. Tlie aldehydes and ketones by means ol the Mannicli reaction oil-bath surrounding the flask \vas heated to 130-1630' f ~ i two methods were used. 111the first method the alkyl- seven hours. The reaction iiiikture tlicn was couled, aiid arid excc~:, piperidine hydrochloritlc, paraforrnaltleliydc, a1id the water added to dissolve the potassiuiii cliloriti~~ proper aldehyde or k e t o i i c were allowed to react i i i isoamyl potassium carLoiiate. Tlic nristurc was exti-acted with alcohol. I n the second method water was used as the ether, ar!d the ether layer dried and distilled. A yirlcl of 10 g. of the desired alcohol was obtained. solvent. The following examples illustrate both methods. (2a) 4-(4-Methylpiperidino) -butanol-2 .-In a 200-nil. In general, for the compounds prepared in this work, the flask equipped with a reflux condenser were placed 10 g. aqueous medium gave the better results. (1) 4-(3-Methylpiperidino) Lbutanone-2 .-Into a 500- of 4-(4-methylpiperidino) -butanone-Z, and 70 ml. of inl. flask, equipped with a stirrer and dropping funnel arid absolute ethyl alcohol. To this solution 10 g. of sodium heated by means of au oil-bath, were placed 40 g. of 8- was added ovt'r a pcxriod of fifteen minutes. 1 he .elution tiirrictl dark r ( d 011 the fir\f addition o i . ~ r r l i u i i i . ;Zii acitlitional 30 i i i l . of alco11ol'\viis atltled ati(1 1 1 1 ~ .r ~ x t i o i i (5) Adkins, "Reactious uf 1Iydrcr~c11,"Utiiveraity ILI Wiscotisin I'res8, Madison. Wisconsin, 1937, pi>.64-67. iiristure heater1 uiitil all the soriiuiii dissolved ; this usually required about twenty niitiutch. Thc iiiixture was ~ [ ~ o l c d , ( 6 ) "Organic Syntheses." Coll. Vol. I , 2ud a , 533 , (1041) was obtained from the IEastman Kodak Co. ; 4-n-amylpiperidine was furnished by Reilly Tar and Chemical Corporation, Indianapolis, Indiana. The other alkylpiperidines were prepared by the hydrogenation of the corresponding alkylpyridines over Raney nickel according to the procedure described by Adkins.6 Each hydrogenation product was fractionated through a 10-plate Fenske column packed with glass helices and a sample having a constant boiling point and index of rcfraction collected. Thcsc propcrties are listed in Table 11; the yields of the alkylpiperidines with such properties varied from 4 5 4 6 % .
Alkylpiperidines.-2,3-Dimethylpiperidine
LOCAL ANESTHETICS DERIVED FROM SUBSTITUTED PIPERIDINOALCOHOLS 2597
Ilec., 19 LG
TABLE IV Ri
METHYLPIPERIDINOALDEHYDES AND KETONES, R-CjH~N--CH&20R,
I
Rz R
2-CH3
Ra
R?
111
E
H
B. p . , "C.
CHa
(mm.)
nmo
83 (6)
1.4660
3-CH:
€7
H
CH3
74 (2)
1.4621
4-CHd
H-
H
CHa
72 ( 2 )
1.4613
4-CHa 4-CH3 I-CH?
CHa CzHs CH3
CH3 H H
H H CH3
64 (3) 86 (2) 85 (2)
1.4573 1.4655 1.4623
and 60 ml. of water slowly added. After saturation of the aqueous solution with sodium chloride, the reaction mixture was extracted with ether. The ether layer, after drying and distillation, yielded 3.3 g. of the desired alcohol; 3 g. of 4-methylpiperidine also was obtained. (2b) 4-(4-Methylpiperidino) -3-methylbutanol-2 .-To a solution of 16 g. of the hydrochloride of 4-(4-methylpiperidino) -3-methylbutanone-2 in 100 ml. of ethyl alcohol was added 0.7 g. of Adams platinum oxide catalyst. This mixture was shaken a t room temperature under a pressure of two atmospheres of hydrogen for twenty-three hours. The catalyst then was filtered off, the alcohol evaporated, and the residue dissolved in water. The aqueous solution was made basic with sodium hydroxide and extracted with ether. The ether layer, after drying and distillation, yielded 4.5 g. of the desired aminoalcohol. (2c) 2,2 -Dimethyl-3- (4-methylpiperidino) -propanol-I .In a 200-ml. flask were placed 18 g. of 2,2-dimethyl-3-(4-
li
'
-CH2C HzCH?OH ---CH,CH2CH,OH CHTCHzCHzOH -CHzCHzCHpOH CHzCH2CHzOH ---CHzCHzCHzOH -.CHyCHyCH2OH
Method of prep.
1 2 1 2 1 2 2 1 2
B p,OC lmm)
XmD
1 4i80 1 4708 1.4699 1.4754 1.4729 1 4719 1.4838
13I (9) 134 (7) 148 (61 115 (45) 133 (8) 87 (4)
I 1778 1,4799 1 4797 1.4622 1.4792 1.4630
--CHzCHzCH(OH)CHI
111 (8)
1.4608
Formula
28
CioHipNO
8.28
8.11
CioHieKO
8.28
8.59
CioHigKO
8.28
8.48
CiiHziNO CiiHziNO CLIHZINO
7.64 7.64 7.64
7.73 7 70 7.84
29 45 38 52 38 45 12 26
---CH2CHzCH (OH)CH3
98 ( 5 )
1.4598
149 (10) 100 (3) 101 ( 2 )
1.4800 1.4590 1.4700
--CH2C(CHa)zCHsOH 72 ( 2 ) 167 (13) --CHz (CHz)r CHzOH ---CH(n-CiH,)CH(CzH~)CH~OH 166 (24)
1.4600 1.4780 1.4667
Method Y i e l d , of prep. %
lh Ib lb lb Ib Ib la lb lb 11,
111 3 lb 2a
2c 2a 2b
2c --CHz(CHz)aCHzOH --CHzCH(CH,)CH(OH) CHI --CHzCH(CzH5) CH2OH
Analyses, % N Calcd. Found
% '
methylpiperidino) -propionaldehyde, 100 ml. of isopropanol, and 14 g. of aluminum isopropoxide. The flask was attached to a Fenske column and its contents heated t o refluxing. The head temperature began to drop immediately, indicating the formation of acetone, which was removed as it formed. Aoftertwo hours of refluxing the head temperature rose to 82 , the boiling point of isopropanol. Water then was added t o the residue in the flask, and the mixture was extracted with ether. After drying, tlic ether layer was distilled and 10 g. of the desired aminoalcohol was obtained. (3) 3-(2-Methylpiperidino) -propanol-2.-To a solution of 125 ml. of methanol and 99 g. of a-pipecoline cooled to -5 O was added, with stirring, 58 g. of propylene oxide over a period of thirty minutes. The reaction flask then was well packed in ice, and the mixture allowed t o stand. A\ the ice melted, the temperature in the reaction mixturt wa5 allowed t o come to room teniperaturc over a period of
112 (1.51 114 (16) 110 (13) 111 (8) 129 (16) 138 (24) 149 (30)
CHiCH2CH.OH CHJCHiCHjOH CHJCH2CH2OH CHzCH(CH3)OH CHJ(CH2j2CHZOH CH2CH>CH(OH)CHa
Yield,
2a 2c Ib 2b 2a 2c 2c 111 lb
60 70 70 58 50 69 51 57 11 37 3; 85 31 9 0 36 63 0 32 0 61 33 42 0 55 62 20
Analyses,
